Early this year, a large phase 3 outcomes trial of the omega-3 fatty acid formulation known as omega-3 carboxylic acid (Epanova) in patients at high risk of cardiovascular events was stopped early due to futility.
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Now detailed results of that Cleveland Clinic-led trial, known as STRENGTH, have been reported in a late-breaking science session at the American Heart Association’s virtual Scientific Sessions 2020. The findings, which were simultaneously published online in the Journal of the American Medical Association, are giving rise to broader questions about the administration of omega-3 fatty acids for prevention of cardiovascular disease.
The context for STRENGTH
Omega-3 carboxylic acid (CA) is a carboxylic acid formulation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that offers greater bioavailability than standard omega-3 ethyl ester formulations.
The STRENGTH trial was designed in the context of substantial interest in the potential benefits of omega-3 fatty acids on cardiovascular health. Observational studies have shown dietary consumption of fatty fish or omega-3 fatty acids to be inversely related to cardiovascular events, and circulating levels of EPA and DHA show a similar inverse association with cardiovascular risk.
Early randomized trials used low doses of omega-3 fatty acids that failed to substantially raise EPA or DHA levels. In contrast, some recent trials have employed higher doses and reported cardiovascular benefits, including the REDUCE-IT trial that compared icosapent ethyl 4 g/d with mineral oil placebo among 8,179 statin-treated patients at high cardiovascular risk. In that trial, icosapent ethyl was associated with a significant reduction in cardiovascular events. These findings were controversial, however, because mineral oil had unfavorable effects on cholesterol and markers of inflammation, which may have exaggerated the apparent benefit of icosapent ethyl.
In view of the fact that 4 g/d of omega-3 CA yields similar elevations in plasma EPA as icosapent ethyl while also increasing DHA levels and producing dose-dependent reductions in plasma triglycerides, omega-3 CA was deemed a good candidate for evaluation in a large outcomes trial.
STRENGTH at a glance
The STRENGTH trial, which was organized by the Cleveland Clinic Coordinating Center for Clinical Research (C5Research), was designed as a large-scale cardiovascular outcomes trial. A total of 13,078 patients at high cardiovascular risk were enrolled at 675 academic and community hospitals across six continents. Participants were randomized in a double-blind fashion to receive 4 g daily of omega-3 CA or corn oil, which was intended to serve as an inert comparator, in addition to usual background therapies, including statin therapy.
The primary endpoint was a composite of major adverse cardiovascular events: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary artery revascularization and hospitalization for unstable angina.
After 1,384 patients had experienced a primary endpoint event, the trial was stopped at the recommendation of the independent data monitoring committee based on evidence of a low chance of clinical benefit and a statistically significant increase in atrial fibrillation in the omega-3 CA arm compared with the corn oil arm (2.2% vs. 1.3%; P < 0.001). By trial closeout, a primary endpoint event occurred in 785 patients treated with omega-3 CA (12.0%) compared with 795 patients receiving corn oil (12.2%) (P = 0.84). This lack of benefit occurred despite a 268% increase in plasma EPA levels in the omega-3 CA arm.
Broader study of omega-3 fatty acids is needed
The STRENGTH investigators concluded that this omega-3 fatty acid formulation did not affect the incidence of major adverse cardiovascular events in statin-treated patients at high cardiovascular risk, but the findings also may raise broader issues.
“These results have prompted the question of why the STRENGTH trial was neutral while the REDUCE-IT trial was favorable,” says Steven Nissen, MD, Chief Academic Officer of Cleveland Clinic’s Heart, Vascular & Thoracic Institute and the study’s senior author. “Compared with mineral oil used in the previous trial, corn oil did not raise levels of LDL cholesterol or markers of inflammation, suggesting that it was a truly neutral placebo.”
“The question of whether administration of omega-3 fatty acids plays a role in the prevention of cardiovascular disease has been investigated with varying results,” notes the study’s second author, Michael Lincoff, MD, Vice Chair for Clinical Research in Cleveland Clinic’s Department of Cardiovascular Medicine and Director of C5Research. “The STRENGTH trial showed a 69% increase in atrial fibrillation in the omega-3 CA treatment group, which creates some uncertainty whether there is net benefit or harm with administration of any omega-3 fatty acid formulation. Given that two large clinical trials have now demonstrated a greater incidence of atrial fibrillation with high-dose omega-3 fatty acid administration, this observation requires further study.”
“These results suggest that a review of the entire class of ‘fish oil’ products is warranted to determine what labelling changes might be appropriate for these products, including whether high-dose fish oil supplements truly provide benefit, given the risk of atrial fibrillation,” adds Dr. Nissen. “These findings also have implications for over-the-counter fish oil supplements since many patients take large doses to avoid the expense of prescription drugs.”
“The STRENGTH trial shows us the importance of placebo,” notes Leslie Cho, MD, Co-Section Head of Preventive Cardiology and Rehabilitation at Cleveland Clinic, who wasn’t involved in the study. “It is intriguing that the placebo in REDUCE-IT increased ultrasensitive C-reactive protein and LDL cholesterol while the placebo in STRENGTH was neutral.”
“Almost 20 million people in the U.S. take fish oil supplements, mostly because these products are advertised to reduce cardiovascular risk and claim unproven health benefits,” observes Dennis Bruemmer, MD, PhD, Director of Cleveland Clinic’s Center for CardioMetabolic Health. “The STRENGTH trial adds to the increasing evidence that fish oil supplementation, particularly when added to recommended statin therapy in high-risk patients, has no beneficial effect on cardiovascular risk. With respect to lipid lowering, the cornerstone of preventive care in high-risk patients remains statin treatment and medical nutrition therapy (to include a Mediterranean diet), which both have proven cardiovascular benefit.”